rs5445

chr12-6847016-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002075.4(GNB3):c.*118C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 658,528 control chromosomes in the GnomAD database, including 4,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (2012 hom., cov: 33)
  • Exomes 𝑓: 0.044 (2622 hom.)
• Consequence: GNB3 NM_002075.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.286

Genes affected

GNB3 (HGNC:4400): (G protein subunit beta 3) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit which belongs to the WD repeat G protein beta family. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. A single-nucleotide polymorphism (C825T) in this gene is associated with essential hypertension and obesity. This polymorphism is also associated with the occurrence of the splice variant GNB3-s, which appears to have increased activity. GNB3-s is an example of alternative splicing caused by a nucleotide change outside of the splice donor and acceptor sites. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Jul 2014]

CDCA3 (HGNC:14624): (cell division cycle associated 3) Predicted to be involved in cell division and protein ubiquitination. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 12-6847016-C-T is Benign according to our data. Variant chr12-6847016-C-T is described in ClinVar as [Benign]. Clinvar id is 1260978.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB3	NM_002075.4	c.*118C>T		3_prime_UTR_variant	10/10	ENST00000229264.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB3	ENST00000229264.8	c.*118C>T		3_prime_UTR_variant	10/10	5	NM_002075.4	P1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15280 AN: 152140 Hom.: 1994 Cov.: 33

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.00556

Gnomad OTH AF: 0.0989

GnomAD4 exome AF: 0.0438 AC: 22171 AN: 506270 Hom.: 2622 Cov.: 6 AF XY: 0.0391 AC XY: 10430 AN XY: 266548

Gnomad4 AFR exome AF: 0.281

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.00823

Gnomad4 EAS exome AF: 0.325

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.00198

Gnomad4 NFE exome AF: 0.00552

Gnomad4 OTH exome AF: 0.0538

GnomAD4 genome AF: 0.101 AC: 15346 AN: 152258 Hom.: 2012 Cov.: 33 AF XY: 0.101 AC XY: 7514 AN XY: 74462

Gnomad4 AFR AF: 0.275

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00556

Gnomad4 OTH AF: 0.0997

Alfa AF: 0.0284 Hom.: 593

Bravo AF: 0.119

Asia WGS AF: 0.127 AC: 443 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	9.0
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5445; hg19: chr12-6956180; COSMIC: COSV57529079; COSMIC: COSV57529079;